Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, United Kingdom.
Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17392-7. doi: 10.1073/pnas.1310519110. Epub 2013 Oct 7.
Extensive regeneration of the vertebrate body plan is found in salamander and fish species. In these organisms, regeneration takes place through reprogramming of differentiated cells, proliferation, and subsequent redifferentiation of adult tissues. Such plasticity is rarely found in adult mammalian tissues, and this has been proposed as the basis of their inability to regenerate complex structures. Despite their importance, the mechanisms underlying the regulation of the differentiated state during regeneration remain unclear. Here, we analyzed the role of the tumor-suppressor p53 during salamander limb regeneration. The activity of p53 initially decreases and then returns to baseline. Its down-regulation is required for formation of the blastema, and its up-regulation is necessary for the redifferentiation phase. Importantly, we show that a decrease in the level of p53 activity is critical for cell cycle reentry of postmitotic, differentiated cells, whereas an increase is required for muscle differentiation. In addition, we have uncovered a potential mechanism for the regulation of p53 during limb regeneration, based on its competitive inhibition by ΔNp73. Our results suggest that the regulation of p53 activity is a pivotal mechanism that controls the plasticity of the differentiated state during regeneration.
脊椎动物身体形态的广泛再生存在于蝾螈和鱼类物种中。在这些生物体中，再生通过分化细胞的重编程、增殖和随后的成年组织再分化来进行。这种可塑性在成年哺乳动物组织中很少见，这被认为是它们无法再生复杂结构的基础。尽管它们很重要，但在再生过程中调节分化状态的机制仍不清楚。在这里，我们分析了肿瘤抑制因子 p53 在蝾螈肢体再生中的作用。p53 的活性最初降低，然后恢复到基线。它的下调对于芽基的形成是必需的，而上调对于再分化阶段是必需的。重要的是，我们表明 p53 活性的降低对于有丝分裂后分化细胞的细胞周期再进入是至关重要的，而增加则是肌肉分化所必需的。此外，我们还发现了一种基于 ΔNp73 竞争抑制的 p53 在肢体再生过程中调节的潜在机制。我们的结果表明，p53 活性的调节是控制再生过程中分化状态可塑性的关键机制。
